# Dicer Is Involved in Cytotoxicity and Motor Impairment Induced by TBPH Deficiency

## TL;DR

This study shows that TBPH, a protein linked to ALS, regulates Dicer proteins, which are important for miRNA production and motor function in fruit flies.

## Contribution

The study reveals a novel functional link between TBPH and Dicer in regulating miRNA biogenesis and motor impairment in an ALS model.

## Key findings

- TBPH knockout reduces DCR-1 and DCR-2 mRNA and protein levels in Drosophila.
- DCR-1/DCR-2 overexpression worsens eye damage in TBPH-deficient flies in a sex-dependent manner.
- Pharmacological Dicer activation reverses locomotor defects in TBPH-deficient flies.

## Abstract

TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS), possibly associated with a role in miRNA biogenesis, which is still not fully understood. Herein we investigated the impact of the Drosophila homolog of TDP-43, TBPH, on genes related to miRNA biogenesis. A TBPH knockout significantly reduced mRNA transcription and protein levels of DCR-1 and DCR-2, whereas an overexpression of DCR-1 and DCR-2 in a TBPH knockdown background exacerbated compound eye damage, with variations in severity that were sex-dependent. Neuronal TBPH RNAi consistently shortened lifespan, with males and females exhibiting distinct survival profiles. DCR-1 and DCR-2 knockdown worsened the locomotor defects induced by TBPH deficiency, thus reinforcing the functional link between TBPH and DCR. In TBPH-deficient flies, the pharmacological activation of Dicer promoted reverse locomotion behavior, with a preference for backward movement. Overall, we show that TBPH is a key regulator of DCR protein expression, highlighting its conserved role in miRNA dysregulation associated with motor function and cytotoxicity in ALS-like pathology in Drosophila models.